Relaxed Selection During a Recent Human Expansion 20 Keywords: Range Expansion, Quebec, Mutation Load, Genetic Drift 21 * Equal Contribution

Genetics: Early Online, published on November 29, 2017 as 10.1534/genetics.117.300551 1 Relaxed selection during a recent human 2 expansion 3 4 5 Peischl, S.1,2,3*, Dupanloup, I.1,2,4*, Foucal, A.1,2, Jomphe, M.5, Bruat, V.6, Grenier, J.-C.6, Gouy, A. 1,2, 6 Gilbert, K.J. 1,2, Gbeha, E.6, Bosshard, L.1,2, Hip-Ki, E.6, Agbessi,M.6, Hodgkinson, A.6,7, Vézina, H.5, 7 Awadalla, P.6,8, and Excoffier, L.1,2 8 1 9 CMPG, Institute of Ecology an Evolution, University of Berne, 3012 Berne, Switzerland 2 10 Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland 3 11 Interfaculty Bioinformatics Unit, University of Berne, 3012 Berne, Switzerland 12 4 Swiss Integrative Center for Human Health SA, 1700 Fribourg, Switzerland 5 13 Balsac Project, University of Quebec at Chicoutimi, Saguenay, Canada 6 14 Hôpital Ste-Justine, University of Montréal, Montréal, Canada 7 15 Department of Medical and Molecular Genetics, Guy's Hospital, King’s College London, London, UK 8 16 Ontario Institute for Cancer Research, Department of Molecular Genetics, University of Toronto, 17 Toronto Canada 18 19 Running title: Relaxed selection during a recent human expansion 20 Keywords: range expansion, Quebec, mutation load, genetic drift 21 * Equal contribution 22 Correspondence 23 Stephan Peischl & Laurent Excoffier 24 CMPG, Institute of Ecology and Evolution 25 University of Berne 26 Baltzerstrasse 6 27 3012 Berne, Switzerland 28 Email: [email protected] 29 [email protected] Copyright 2017. 30 Abstract 31 Humans have colonized the planet through a series of range expansions, which deeply impacted 32 genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations 33 on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians 34 who colonized Quebec in the 17th century. We used historical information and records from ~4000 35 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front 36 and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity 37 reveals that i) both new and low frequency variants are significantly more deleterious in front than in 38 core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) 39 front individuals are two times more likely to be homozygous for rare very deleterious mutations 40 present in Europeans. These differences have emerged in the past 6-9 generations and cannot be 41 explained by differential inbreeding, but are consistent with relaxed selection mainly due to higher rates 42 of genetic drift on the wave front. Demographic inference and modeling of the evolution of rare variants 43 suggest lower effective size on the front, and lead to an estimation of selection coefficients that increase 44 with conservation scores. Even though range expansions had a relatively limited impact on the overall 45 fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in 46 recently settled regions of Quebec. 2 47 Introduction 48 The impact of recent demographic changes or single bottlenecks on the overall fitness of 49 populations is still highly debated (LOHMUELLER et al. 2008; FU et al. 2014; LOHMUELLER 2014; SIMONS et al. 50 2014; DO et al. 2015; HENN et al. 2015; GRAVEL 2016; HENN et al. 2016). Simulation and theoretical 51 approaches suggest that populations on expanding wave fronts experience strong genetic drift (PEISCHL 52 et al. 2013; PEISCHL et al. 2015), leading to relaxed selection (GRAVEL 2016) resulting in the build-up of 53 expansion load (PEISCHL et al. 2013). The main reason for this expansion load is that low population 54 densities and strong genetic drift at the wave front promote the genetic surfing of both neutral and 55 selected variants (PEISCHL et al. 2013). This relatively inefficient selection on the wave front leads to the 56 preservation of many new mutations, unless very deleterious (PEISCHL et al. 2013), and it shifts the site 57 frequency spectrum (SFS) of standing variants, thus increasing the contribution of (partially) recessive 58 variants to mutation load (PEISCHL AND EXCOFFIER 2015). After a range expansion, both a decrease of 59 diversity and an increase in the recessive mutation load with distance from the source is expected 60 (KIRKPATRICK AND JARNE 2000; PEISCHL AND EXCOFFIER 2015). This pattern has recently been shown to occur 61 in non-African human populations, where a gradient of recessive load has been observed between 62 North Africa and the Americas (HENN et al. 2016). Whereas the bottleneck out of Africa that started 63 about 50 Kya (e.g. GRAVEL et al. 2011) must have created a mutation load, the exact dynamics of this 64 load increase due to the expansion process is still unknown. It is also unclear if a much more recent 65 expansion could have had a significant impact on the genetic load of populations. 66 The settlement of Quebec can be considered as a series of demographic and spatial expansions 67 following initial bottlenecks. The majority of the 6.5 million French Canadians living in Quebec are the 68 descendants of about 8,500 founder immigrants of mostly French origin (CHARBONNEAU et al. 2000; 69 LABERGE et al. 2005). This French immigration started with the founding of a few settlements along the 70 Saint Laurence river at the beginning of the 17th century (CHARBONNEAU et al. 2000). Most new 71 settlements were restricted to the Saint Laurence Valley until the 19th century, after which remote 72 territories began to be colonized. Bottlenecks and serial founder effects occurring during range 73 expansions are thought to have profoundly affected patterns of genetic diversity, leading to large 74 frequency differences when compared to the French source population (LABERGE et al. 2005). Even 75 though the French Canadian population has expanded 700 fold in about 300 years, its genetic diversity is 76 actually not what is expected in a single panmictic, exponentially growing population, as allele 77 frequencies have drifted much more than expected in a fast growing population (HEYER 1995; HEYER 78 1999). It has been shown that genetic surfing (KLOPFSTEIN et al. 2006; PEISCHL et al. 2016) has occurred 79 during the recent colonization of Saguenay-Lac St-Jean area (MOREAU et al. 2011), and that the fertility of 3 80 women on the wave front was 25% higher than of those living in the core of the settlement, giving them 81 more opportunity to transmit their genes to later generations. In addition, female fertility was found to 82 be heritable on the front but not on the core (MOREAU et al. 2011), a property that further contributes to 83 lower the effective size of the front population (AUSTERLITZ AND HEYER 1998; SIBERT et al. 2002) and to 84 enhance drift on the wave front. Social transmission of fertility (AUSTERLITZ AND HEYER 1998) and genetic 85 surfing during range expansions or a combination of both (MOREAU et al. 2011) have been proposed to 86 explain a rapid increase of some low frequency variants. It thus seems that differences in allele 87 frequencies between French Canadians and continental Europe are due to a mixture of the random 88 sampling of initial immigrants (founder effect) and of strong genetic drift having occurred in Quebec 89 after the initial settlement, resulting in a genetically and geographically structured population of French 90 Canadians (BHERER et al. 2011). 91 The demographic history of Quebec has not only affected patterns of neutral diversity, but also 92 the prevalence of some genetic diseases independently from inbreeding (DE BRAEKELEER 1991; HEYER 93 1995; LABERGE et al. 2005; YOTOVA et al. 2005), as well as the average selective effect of segregating 94 variants (CASALS et al. 2013). Even though French Canadians have fewer mutations segregating in the 95 population than the French, these mutations are found at loci which are, on average, much more 96 conserved, and thus are potentially more deleterious than those segregating in the French population 97 (CASALS et al. 2013). Recurrent founder effects, low densities and intergenerational correlation in 98 reproductive success could all contribute to increase drift and reduce the efficacy of selection on 99 expanding wave fronts, and thus lead to the development of a stronger mutation load (PEISCHL et al. 100 2013). Furthermore, even short periods of increased drift and relaxed selection can affect the efficacy of 101 selection in future generations (GRAVEL 2016), resulting in differential rates of purging in front and core 102 populations. It is therefore likely that the excess of low frequency deleterious variants observed in 103 French Canadian individuals (e.g. CASALS et al. 2013), could be at least partly due to the expansion 104 process rather than to the sole initial bottleneck. 105 To better understand and quantify the effect of a recent expansion process on the amount and 106 pattern of deleterious genetic variation, we screened the ascending genealogies of 3916 individuals 107 from the CARTaGENE cohort (AWADALLA et al. 2013) that were linked to the BALSAC genealogical 108 database (http://balsac.uqac.ca/). Using stringent criteria on the quality of genealogical information (see 109 Methods), we selected 51 (front) individuals whose ancestors were as close as possible to the front of 110 the colonization of Quebec, and 51 (core) individuals whose ancestors were as far as possible from the 111 front (see Methods, Fig. 1, and Supporting Animation S1 and S2). We then sequenced these 102 112 individuals at very high coverage (mean 89.5X, range 67X-128X) for 106.5 Mb of exomic and UTR 4 113 regions and contrasted their genomic diversity to detect if sites with various degrees of conservation 114 and deleteriousness have been differentially impacted by selection.

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